Metastatic melanoma is an aggressive tumor with a poor prognosis. Critical biologic features of melanoma metastasis are the acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma metastasis, a genome-wide search using BAC array CGH and SNP arrays in a series of metastatic melanoma samples identified increased copy numbers of GAB2 located on 11q14.1. GAB2 is an adaptor molecule that potentiates activation of various signal transduction cascades such as RAS-ERK and PI3K-AKT pathways and has recently been implicated in human cancer; however, its role in melanoma is undefined. In our Preliminary Studies, we found GAB2 as either amplified (~11%) and/or overexpressed (~47%) in melanoma. Clinical correlative studies identified GAB2 as a novel genetic event amplified in a subset of acral and mucosal melanomas independent of genetic alterations in BRAF, NRAS, and KIT. GAB2 protein expression correlated with clinical melanoma progression and higher levels of expression were seen in metastatic melanomas compared to primary melanoma (p=0.0137) and melanocytic nevi (p=0.004). We found that overexpression of GAB2 potentiates, whereas silencing of GAB2 reduces, migration and invasion of melanoma cells. GAB2 mediated hyperactivation of PI3/PDK1/AKT signaling in the absence of growth factors, and inhibition of the PI3K-AKT pathway decreased GAB2-mediated tumor cell migration and invasion potential. Furthermore, GAB2 stimulated Cdc42-GTPase activity suggesting its potential as a regulator of Rho family GTPases. These studies demonstrate a previously undefined role for GAB2 in melanoma metastasis and highlight the significance of GAB2 adaptor molecule, critical for various signal transduction pathways, in melanoma. However, the mechanisms of GAB2-mediated tumor cell motility and invasion in cancer are uncharacterized. Moreover, the role of GAB2 in melanoma is unexplored. In the proposed studies, we plan probe mechanistic insights into GAB2-mediated signaling in melanoma, mechanisms of tumor cell motility and invasion, and cooperation of GAB2 with additional genetic events during tumor progression and metastasis. We expect to define the biological significance of GAB2 in melanoma that will provide the basis for development of targeted therapies. PUBLIC HEALTH RELEVANCE: GAB2 is an adapter protein with critical functions in signal transduction pathways and has recently been implicated to play a role in human cancer. This proposal involves studying the contribution of GAB2 in melanoma to provide a basis whether its targeting would be therapeutically beneficial.